Use of heterocyclic compounds

ABSTRACT

PCT No. PCT/EP95/02782 Sec. 371 Date Jan. 14, 1997 Sec. 102(e) Date Jan. 14, 1997 PCT Filed Jul. 14, 1995 PCT Pub. No. WO96/02246 PCT Pub. Date Feb. 1, 1996The present invention relate to the use of heterocyclic compounds of the following formula:Het-A-B-Arwhere Het, A, B and Ar have the meanings stated in the description. The compounds according to the invention have a high affinity for the dopamine D3 receptor and can therefore be used to treat disorders which respond to dopamine D3 ligands.

This application is a 371 of PCT/EP95/02782, filed Jul. 14, 1995, which claims priority of Fed. Ref. Germany Application P 44 25 146.7, filed Jul. 14, 1994.

The invention relates to the use of heterocyclic compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D₃ receptor ligands.

Compounds of the type under discussion here and having physiological activity have been disclosed. Thus, U.S. Pat. No. 4,404,382 describes corresponding imidazole compounds with antiallergic activity.

U.S. Pat. No. 3,362,956 likewise describes imidazole compounds of this type. The latter have adrenolytic and anticonvulsant activity.

DE-A-22 58 033 describes pyrazole compounds with central depressant activity.

DE-A-27 17 415 describes furan, thiophene, oxazole and thiadiazole compounds which can be used to treat hypersensitivity disorders.

Neurous obtain their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.

There is confirmed evidence of the presence of dopamine and its physiological function as neurotransmitter. Cells which respond to dopamine are involved in the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.

By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D₁ and D₂ receptors.

Sokoloff et al., Nature 1990, 347: 164-151, found a third subtype, namely D₃ receptors. They are expressed mainly in the limbic system. The D₃ receptors differ structurally from the D₁ and D₂ receptors in about half the amino acid residues.

The effect of neuroleptics has generally been ascribed to their affinity for D₂ receptors. Recent receptor-binding studies have confirmed this. These showed that most dopamine antagonists, such as neuroleptics, have high affinity for D₂ receptors but only low affinity for D₃ receptors.

The prior art compounds described above are such D₂ receptor agonists and antagonists.

It has now been found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D₃ receptor and only a low affinity for the D₂ receptor. They are thus selective D₃ ligands.

The present invention therefore relates to the use of compounds of the formula I:

    Het--A--B--Ar

where

A is a straight-chain or branched C₁ -C₁₈ -alkylene group which may comprise at least one group which is selected from among O, S, NR⁴, CONR⁴, NR⁴ CO, COO, OCO and a double or triple bond,

B is a radical of the formula: ##STR1## Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have one to four substituents which are, independently of one another, selected from among OR⁴, C₁ -C₈ -alkyl, C₂ -C₈ -alkenyl, C₂ -C₈ -alkynyl, halogen, CN, CO₂ R ⁴, NO₂, SO₂ R⁴, SO₃ R⁴, NR⁴ R⁵, SO₂ NR⁵ R⁵, SR⁴, CF₃, CHF₂, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring having 1 to 3 hetero atoms which are selected from among O, S and N, where the carbocyclic or the heterocyclic ring is unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃, and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above,

Het is a group which is selected from among ##STR2## where R¹, R² and R³ are, independently of one another, H, halogen, OR⁵, NR⁴ R⁵ ₁, SR⁴, CF₃, CN, CO₂ R⁴ or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen,

R⁴ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₃ -alkyl or halogen;

R⁵ has the meanings indicated for R⁴ or is COR⁴ or CO₂ R⁴ ;

R⁸ has the meanings indicated for R⁵, and the salts thereof with physiologically tolerated acids,

for the production of a pharmaceutical composition for treating disorders which respond to dopamine D₃ receptor antagonists or agonists.

The compounds according to the invention are selective dopamine D₃ receptor ligands which intervene regioselectively in the limbic system. Because of their low affinity for the D₂ receptor, they have fewer side effects than the classical neuroleptics which are D₂ antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D₃ receptor antagonists or agonists, eg. to treat disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disturbances and nausea and as antihistamines.

For the purpose of the present invention, the following terms have the meanings indicated below:

Alkyl (also in radicals such as alkoxy, alkylamino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group may have one or more substituents which are selected, independently of one another, from among OH and OC₁ -C₈ -alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, etc.

Alkylene stands for straight-chain or branched radicals with, preferably, 2 to 10 carbon atoms, particularly preferably 3 to 8 carbon atoms and, in particular, 3 to 6 carbon atoms.

The alkylene groups may comprise at least one of the abovementioned groups. This can--just like the double or triple bond mentioned--be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the heterocyclic radical. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.

Halogen is F, Cl, Br, I and, in particular, Cl, Br, I.

The radical Ar may have one, two, three or four substituents. The substituents may be located at any position on the phenyl ring. Preferably, however, at least one is in the m position.

Preferably, they are, independently of one another, selected from among H, C₁ -C₈ -alkyl, OC₁ -C₈ -alkyl, CHF₂, CF₃, CN, halogen, SO₂ OR⁴ and CO₂ R⁴.

Ar preferably has at least one substituent and is, in particular, ##STR3## where D¹, D² and D³ are, independently of one another, CH or N, and X and Y are H or have the meanings indicated above or below.

D¹, D² and D³ are preferably CH or D¹ is N and D² and D³ are CH. When one of the substituents of the radical Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.

When one of the substituents of the radical Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclophenyl or cyclohexyl radical.

When one of the substituents of the radical Ar is C₁ -C₈ -alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.

When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.

A preferred embodiment comprises the compounds of the formula I where A is C₁ -C₈ -alkylene which may comprise an oxygen or sulfur atom or the group CONR⁴, in particular O or S.

Another preferred embodiment comprises the compounds of the formula I where Het is a group of the following general formulae: ##STR4##

Another preferred embodiment comprises the compounds of the formula I where Bet is a group of the following general formulae: ##STR5##

Another preferred embodiment comprises the compounds of the formula I where Het is a group of the general formulae: ##STR6##

In these, R¹, R², R³ and R⁸ always have the meanings indicated above.

R¹, R² and R³ are preferably, independently of one another, H, NR⁴ R⁵, OR⁵, C₁ -C₈ -alkyl, CO₂ R⁴, CF₃ or halogen.

The Het radical preferably has one or two, in particular one, substituent.

When Het is a pyridine residue, R¹, R² and R³ are preferably selected, independently, from among H, halogen, OR⁵, NR⁴ R⁵, CF₃, CO₂ R⁴ and C₁ -C₈ -alkyl.

When Het is a thiophene residue, R¹ and R² are preferably selected, independently, from among halogen and C₁ -C₈ -alkyl.

When Het is a purine residue, A is preferably S--C₄ -C₇ -alkyl.

In another embodiment, A is a C₃ -C₆ -alkylene group which may comprise S, O or CONR⁴.

X is preferably H, CF₃, CN, halogen, NO₂, CHF₂, C₁ -C₈ -alkyl, in particular C₂ -C₄ -alkyl, SO₂ R⁴ or CO₂ R⁴ and in particular H, CF₃, halogen, CHF₂, C₁ -C₈ -alkyl or CN. X is particularly preferably CF₃. CHF₂ or C₂ -C₄ -alkyl.

Y is preferably C₁ -C₈ -alkyl, in particular C₂ -C₄ -alkyl, or hydrogen.

A particularly preferred embodiment comprises the compounds of the formula Ia: ##STR7## and, in particular, the compounds of the formula Ib: ##STR8## where A, Het, X and Y have the meanings indicated above. In the formulae Ia and Ib in particular X is CF₃ and Y is H or X and Y are both C₁ -C₈ -alkyl.

The invention also embraces the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, volume 10, pages 224 et seq., Birkhauser Verlag, Basle and Stuttgart, 1966.

The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the tautomeric forms in each case.

Those compounds of the formula I which are novel are prepared in a similar manner to the prior art mentioned at the outset, using methods familiar to the skilled worker.

To treat the abovementioned disorders, the compounds according to the invention are administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which contain the compounds according to the invention. These compositions are in the usual solid or liquid pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. The active substances can in these cases be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount of from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1

2-[3-(4-{3-Trifluoromethylphenyl}piperazinyl)propylthio]pyridine ##STR9## a) 1-(3-Chloropropyl)-4-(3-trifluoromethlphenyl)-piperazine

30 g (0.13 mol) of trifluoromethylphenyl-piperazine, 23 g (0.146 mol) of 1-bromo-3-chloropropane and 15 g (0.148 mol) of triethylamine in 200 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction and concentration. The viscous residue was taken up in ethyl acetate, washed with water, dried over MgSO₄ and then concentrated. The resulting residue comprised 39 g of product as yellowish oil (quantitative yield).

b) 2-[3-(4-{Trifluoromethylphenyl}piperazinyl)propylthio]pyridine

1.11 g (10 mmol) of 2-mercaptopyridine, 3.1 g (10.1 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and again extracted with ethyl acetate, and the organic phase was dried over MgSO₄ and concentrated. The residue was purified by chromatography (mobile phase: CH₂ Cl₂ /CH₃ OH═98/2).

2.5 g of product were obtained as yellowish oil (=65% yield).

H-NMR [δ, ppm]: 1.95 (2H); 2.55 (2H); 2.62 (4H); 3.23 (6H); 6.95 (1H); 7.05 (3H); 7.17 (1H); 7.36 (1H); 7.48 (1H); 8.42 (1H)

EXAMPLE 2

2-[5-(4-{3-Trifluoromethylphenyl}piperazinyl)pentylmercapto] pyridine ##STR10## a) 2-(5-Chloropentylmercapto)pyridine

2.78 g (25 mmol) of 2-mercaptopyridine, 4.64 g (25 mmol) of 1-bromo-5-chloropentane and 2.58 g (25.5 mmol) of triethylamine in 100 ml of THF were refluxed for 4 hours. Cooling was followed by filtration with suction, concentration and purification of the residue by chromatography (mobile phase: cyclohexane/ethyl acetate=92/8). 4 g of product were obtained (=74% yield).

b) 2-[5-(4-{3-Trifluoromethylphenyl}piperazinyl)pentylmercapto]pyridine

2.37 g (11 mmol) of 2-(5-chloropentyl-mercapto)pyridine, 2.78 g (12 mmol) of m-trifluoro-methylphenylpiperazine and 1.22 g (12.1 mmol) of triethylamine in 5 ml of DMF were stirred at 90° C. for 5 hours. The mixture was then poured into water and extracted three times with CH₂ Cl₂, followed by drying over MgSO₄ and concentrating. The residue was mixed with methyl t-butyl ether and filtered off with suction, and the mother liquor was concentrated. Purification by chromatography (mobile phase: CH₂ Cl₂ /CH₃ OH═96/4) resulted in 3.0 g of product as oil (=67% yield).

H═NMR [δ; ppm]: 1.5 (4H); 1.75 (2H); 2.4 (2H); 2.6 (4H); 3.2 (2H); 3.25 (4H); 7.0 (1H); 7.1 (3H); 7.2 (1H); 7.35 (1H); 7.45 (1H); 8.4 (1H)

EXAMPLE 3

3-[3- (4-{3-Trifluoromethylphenyl}piperazinyl)propylamino-carbonyl]thiophene ##STR11##

A mixture of 0.76 g (5.9 mmol) of 3-thiophene-carboxylic acid, 1.0 g (6.2 mmol) of carbonyldiizidazole and 1 spatula tip of dimethylaminopyridine in CH₂ Cl₂ was stirred at room temperature for 1/2 h. 1.9 g (5.9 mmol) of N-(3-trifluoromethylphenyl)-N'-(3-aminopropyl)piperazine were added dropwise to this mixture, which was further stirred at room temperature overnight. Aqueous workup was followed by chromatography on SiO₂ (mobile phase: CH₂ _(Cl) ₂ /CH₃ OH═10:1). The resulting oil was dissolved in a little CH₃ OH. Addition of 0.64 g (5.5 mmol) of fumaric acid in CH₂ Cl₂ resulted in 1.3 g of product as white solid. Melting point: 124-125° C.

EXAMPLE 4

2-[2-(4-{3-Trifluoromethylphenyl}piperazinyl)ethylamino-carbonyl]pyridine ##STR12##

0.74 ml of chloroethyl formate was added dropwise to a solution of 0.95 g of 2-pyridinecarboxylic acid and 1.1 ml of NEt₃ in CH₂ Cl₂ at 0° C. After stirring at room temperature for 15 min, the mixture was again cooled and 2 g of N-(3-trifluoromethylphenyl)-N'-(2-aminoethyl)-piperazine were added dropwise. The mixture was then stirred at room temperature for 3 h, washed with H₂ O, NH₄ Cl solution, NaOH and H₂ O, dried over MgSO₄ and concentrated. Recrystallization from ethyl acetate/heptane resulted in 1.9 g of product. Melting point: 108-110° C.

EXAMPLE 5

2-[3-(4-{3-Trifluoromethylphenyl}piperazinyl)propylamino-carbonylmethyl]pyridine ##STR13##

2.87 g of N-(3-trifluoromethylphenyl)-N'-(3-aminopropyl)-piperazine were added dropwise to a solution of 2.34 g of 2-pyridineacetic acid N-hydroxysuccinimide ester in CH₂ Cl₂ while cooling. The mixture was stirred at room temperature overnight and subsequently washed with NaHCO₃ solution and water. The organic phase was separated off and dried with MgSO₄, and the solvent was distilled off. A little CH₃ OH was added to the residue, and then ethereal HCl was added dropwise. 2.0 g of product were obtained as white solid. Melting point: 178-179° C.

The following compounds were synthesized in a similar manner: ##STR14##

    __________________________________________________________________________                                   Physical data                                                                  H-NMR [δ, ppm],-                           Example No.                                                                          Het          A          Melting Point                                    __________________________________________________________________________                        SCH.sub.2 CH.sub.2 CH.sub.2                                                               2.07(2H);2.63(6H);3.22(4H);                                                    3.45(2H);7.08(3H);7.33(1H);                                                    8.22(1H);8.75(1H)                                7                                                                                     ##STR15##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.35(3H);1.92(2H);2.48(3H);                                                    2.65(6H);3.15(2H);3.28(4H);                                                    4.3(2H);7.08(3H);7.35(1H)                        8                                                                                     ##STR16##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.88(2H);2.5(2H);2.55(4H);                                                     3.1(2H);3.2(4H);3.62(3H);                                                      6.93(1H);7.1(4H);7.35(1H)                        9                                                                                     ##STR17##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.95(2H);2.65(6H);3.08(2H);                                                    3.3(4H);7.05(5H);7.36(1H)                        10                                                                                    ##STR18##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.92(2H);2.5(2H);2.6(4H);                                                      3.08(2H);3.24(4H);7.08(SH);                                                    7.36(1H);8.4(2H)                                 11                                                                                    ##STR19##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.0(2H);2.55(2H);2.62(4H);                                                     3.26(4H);4.35(2H);6.63(1H);                                                    6.9(1H);7.1(3H);7.35(1H);  7.53(1H)              12                                                                                    ##STR20##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.1(2H);2.6(6H);3.23(4H);                                                      4.08(2H);6.22(1H);6.8(1H);                                                     7.05(4H);7.32(1H)                                13                                                                                    ##STR21##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.0(2H);2.45(3H);2.6(2H);                                                      2.65(4H);3.25(4H);4.35(2H);                                                    6.52(1H);6.7(1H);7.08(3H);                                                     7.35(1H);7.45(1H)                                14                                                                                    ##STR22##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.9(2H);2.55(2H);2.65(4H);  3.1                                                (2H);3.3(4H);7.1(5H);  7.35(1H);8.1(1H)          15                                                                                    ##STR23##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.0(2H);2.55(2H);2.63(4H);                                                     3.25(4H);4.35(2H);6.7(1H);                                                     7.05(3H);7.35(IH);7.52(1H);  8.08(1H)            16                                                                                    ##STR24##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.0(2H);2.6(2H);2.65(4H);                                                      3.25(4H);4.25(4H);6.1(2H);                                                     7.1(3H);7.35(2H)                                 17                                                                                    ##STR25##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               1.98(2H);2.58(2H);2.65(4H);                                                    3.3(6H);7.1(3H);7.3(1H);                                                       7.37(1H);7.66(1H);8.66(1H)                       18                                                                                    ##STR26##   SCH.sub.2 CH.sub.2 CH.sub.2                                                               2.0(2H);2.55(2H);2.6(4H);                                                      3.23(6H);3.93(3H);7.05(4H);                                                    7.35(1H);8.2(1H);8.55(1H)                        19                                                                                    ##STR27##   OCH.sub.2 CH.sub.2 CH.sub.2                                                               2.02(2H);2.6(6H);3.22(4H);                                                     4.36(2H);6.75(1H);6.85(1H);                                                    7.05(3H);7.35(1H);7.55(1H);  8.15(1H)            20                                                                                    ##STR28##   CH.sub.2 CH.sub.2 CH.sub.2                                                                2.1(2H);2.38(2H);2.65(4H);                                                     3.25(4H);4.1(2H);5.4(1H);                                                      5.83(2H);5.9(1H);7.1(4H);  7.35(1H)              21                                                                                    ##STR29##   CH.sub.2 CH.sub.2 CH.sub.2                                                                1.95(2H);2.4(3H);2.5(2H);                                                      2.6(4H);3.42(4H);4.1(2H);                                                      8.0(1H);6.42(1H);7.05(3H);                                                     7.1(1H);7.35(1H)                                 22                                                                                    ##STR30##   CH.sub.2 CH.sub.2 CH.sub.2                                                                2.0(2H);2.45(2H);2.6(4H);                                                      3.25(4H);4.02(2H);6.15(1H);                                                    6.57(1H);7.1(3H);7.35(3H)                        23                                                                                    ##STR31##   CH.sub.2 CH.sub.2 CH.sub.2                                                                2.0(2H);2.4(2H);2.6(4H);                                                       3.25(4H);4.02(2H);6.55(1H);  7.1                                               (3H);7.3(2H);7.48(1H)                            24                                                                                    ##STR32##   CONHCH.sub.2 CH.sub.2                                                                     197-200° C.  (Hydrochloride)              25                                                                                    ##STR33##   CONHCH.sub.2 CH.sub.2                                                                     208-209° C.                               26                                                                                    ##STR34##   CH.sub.2 CONHCH.sub.2 CH.sub.2                                                            2.52(2H);2.60(4H);3.25(6H);                                                    3.62(2H);6.65(4H);  7.0-7.45(6H);7.75(1H);                                     8.18(1H);8.44(1H)  Fumarate                      27                                                                                    ##STR35##   CH.sub.2 CONHCH.sub.2 CH.sub.2                                                            180-183° C.                               28                                                                                    ##STR36##   CONHCH.sub.2 CH.sub.2                                                                     2.5(3H);2.7(6H);3.3(4H);                                                       3.55(2H);6.55(1H);6.7(1H);                                                     7.1(3H);7.35(2H)                                 29                                                                                    ##STR37##   CONHCH.sub.2 CH.sub.2                                                                     2.68(6H);3.25(4H);3.55(2H);                                                    6.6(1H);6.9(1H);7.1(3H);                                                       7.25(1H);7.35(1H)                                30                                                                                    ##STR38##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            1.86(2H);2.5(2H);2.65(4H);                                                     6.5(1H);7.05(3H);7.3(1H);                                                      7.75(1H);8.01(1H)                                31                                                                                    ##STR39##   CH═CHCONHCH.sub.2 CH.sub.2  trans                                                     230° C.  Dihydrochloride                  32                                                                                    ##STR40##   CH═CHCONHCH.sub.2 CH.sub.2  trans                                                     238-241° C.  Dihydrochloride              33                                                                                    ##STR41##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            198-200° C.  Fumarate                     34                                                                                    ##STR42##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            218-220° C.  Dihydrochloride              35                                                                                    ##STR43##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            182-184° C.  Dihydrochloride              36                                                                                    ##STR44##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            181-182° C.  Dihydrochloride              37                                                                                    ##STR45##   CH.sub.2 CONHCH.sub.2 CH.sub.2                                                            2.45(2H);2.6(4H);3.25(6H);                                                     3.62(2H);6.6(4H);  7.0-7.42(6H);7.75(1H);                                      8.18(1H);8.85(1H)  Fumarate                      38                                                                                    ##STR46##   CH.sub.2 CONHCH.sub.2 CH.sub.2                                                            180-183° C.  Dihydrochloride              39                                                                                    ##STR47##   CONHCH.sub.2 CH.sub.2                                                                     200-201° C.  Dihydrochloride              40                                                                                    ##STR48##   CONHCH.sub.2 CH.sub.2                                                                     178-180° C.  Dihydrochloride              41                                                                                    ##STR49##   CH.sub.2 CONHCH.sub.2 CH.sub.2                                                            148-150° C.  Dihydrochloride              42                                                                                    ##STR50##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            194-195° C.  Dihydrochloride              43                                                                                    ##STR51##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            201-202° C.  Dihydrochloride              44                                                                                    ##STR52##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            179-181° C.  Dihydrochloride              45                                                                                    ##STR53##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            153-155° C.  Dihydrochloride              46                                                                                    ##STR54##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            164-166° C.  Dihydrochloride              47                                                                                    ##STR55##   CONHCH.sub.2 CH.sub.2 CH.sub.2                                                            138-139° C.  Dihydrochloride              48                                                                                    ##STR56##   CONHCH.sub.2 CH.sub.2                                                                     197-200° C.  Dihydrochloride              49                                                                                    ##STR57##   CONHCH.sub.2 CH.sub.2                                                                     208-210° C.  Dihydrochloride              50                                                                                    ##STR58##   S(CH.sub.2).sub.3                                                                         1.9(2H);2.6(BH);3.1(2H);                                                       3.38(4H);6.22(1H);  6.35(1H);7.07(3H);7.3(2H                                   )                                                __________________________________________________________________________

Examples of pharmaceutical forms:

A) Tablets

Tablets of the following composition are compressed in a tabletting machine in a conventional manner:

40 mg of substance from Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silica in submicroscopically fine dispersion)

6.75 mg of potato starch (as 6% strength paste)

B) Sugar-coated tablets

20 mg of substance from Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition comprises 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.

Biological investigations

Receptor-binding studies

Cloned human D₃ receptor-expressing CCL 1.3 mouse fibroblasts obtained from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2148 USA, were used for binding studies.

Cell Preparation

The D₃ -expressing cells were grown in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4, with 10% glycerol) and then incubated in a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200×g for 10 min and the pellet was stored in liquid nitrogen.

Binding assays

For the D₃ receptor-binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of about 10⁶ cells/250 μl of assay mixture and incubated at 30° C. with 0.1 nM ¹²⁵ iodosulpiride in the presence and absence of test substance. The non-specific binding was determined using 10⁻⁶ M spiperone.

After 60 min, the free and the bound radioligand was separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program. In this assay, the compounds according to the invention show very high affinities for the D₃ receptor and good selectivities with respect to the D₂ receptor. 

What is claimed is:
 1. A composition for treating disorders which respond to dopamine D₃ receptor antagonists or agonists which comprises a pharmaceutical aid and an effective amount of a compound of the formula I:

    Het--A--B--Ar

where A is a straigh chain or branched C₃ -C₈ -alkylene group which contains at least one group which is selected from among O, S, NR⁴, CONR⁴, NR⁴ CO, COO, and OCO, B is a radical of the formula: ##STR59## Ar is a phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have one to four substituents selected from the group consisting of OR⁴, C₁ -C₈ -alkyl, C₂ -C₈ -alkenyl, C₂ -C₈ -alkynyl, halogen, CN, CO₂ R⁴, NO₂, SO₂ R⁴, SO₃ R⁴, NR⁴ R⁵, SO₂ NR⁴ R⁵, SR⁴, CF₃, CHF₂, a 5- or a 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or a 6-membered heterocyclic, aromatic or non-aromatic ring having 1 to 3 hetero atoms which are selected from O, S and N, where the carbocyclic or the heterocyclic ring is unsubsfituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃, and where Ar may also be fused to a 5- or 6-membered carbocyclic, aromatic ring or to a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring having 1 to 3 heteroatoms which are selected from O, S and N, where the carbocyclic or the heterocyclic ring is unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃, Het is a group ##STR60## where R¹, R² and R³ are, independently of one another, H, halogen, OR⁵, NR⁴ R⁵, SR⁴, CF₃, CN or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, R⁴ is H or C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, R⁵ is the meaning indicated for R⁴ or is COR⁴ or CO₂ R⁴ ;and the salts thereof with physiologically tolerated acids.
 2. The composition of claim 1 whereA is a C₃ -C₈ -alkylene group which contains O, S or CONR⁴, and Ar is a phenyl or pyridyl which may have one or two substituents selected from the group consisting of H, C₁ -C₈ -alkyl, OC₁ -C₈ -alkyl, CHF₂, CF₃, CN, halogen, SO₂ OR⁴ and CO₂ R⁴.
 3. The composition of claim 5 whereA is a C₃ -C₆ -alkylene group which contains S, O or CONR⁴, and Ar may carry one or two substituents selected from the group consisting of H, CF₃, halogen, C₁ -C₈ -alkyl, OC₁ -C₈ -alkyl and CN, and ##STR61## .
 4. The composition of claim 6 whereR¹, R² and R³ are H, NR⁴ R⁵, OR⁵, C₁ -C₈ -alkyl, CF₃ or halogen, R⁴ is H or C₁ -C₈ -alkyl, and R⁵ is H, C₁ -C₈ -alkyl or OC₁ -C₈ -alkyl.
 5. The composition of claim 1 whereA is a C₃ -C₆ -alkylene group which contains S, O or CONH, ##STR62## Ar may carry one to four substituents selected from the group consisting of H, CHF₂, C₁ -C₄ -alkyl and CF₃.
 6. The composition of claim 1 where ##STR63## X and Y are as defined for the substituents of the radical Ar.
 7. The composition of claim 9 where ##STR64##
 8. The composition of claim 9, where Y is H or C₁ -C₄ -alkyl, andX is CF₃, CHF₂, CN or C₁ -C₄ -alkyl.
 9. A method of treating disorders which respond to dopamine D₃ receptor antagonists or agonists, in which a therapeutically effective amount of a compound as defined in claim 1 is administered to a person requiring such a treatment.
 10. The composition of claim 1 wherein Het is ##STR65## A is S(CH₂)₃. 